RATIONALE: Hypersecretion of corticotropin releasing factor (CRF) has been implicated in both severe anxiety disorders and major depression. Although the role of the CRF1 receptor in the anxiogenic effects of CRF is well supported, the role of CRF2 receptors in anxiety-like behaviors is less clear. In rats, CRF increases the acoustic startle reflex (ASR) via its action in the extended amygdala, providing a putative measure of CRF-mediated anxiogenic activity. OBJECTIVE: To characterize the effect of CRF on ASR in mice and determine the respective roles of CRF1 and CRF2 receptors in CRF-potentiated ASR. METHODS: The present study examined: (1) the time course and dose response functions for the effects of human/rat (h/r)-CRF (0.02-0.6 nmol, ICV (intracerebroventricular)) on ASR in two inbred strains of mice; (2) the effects of the CRF1 receptor antagonist NBI-30775 (20 mg/kg, intraperitoneal) and the CRF2 receptor antagonist Antisauvagine-30 (1-10 nmol, ICV) on CRF-potentiated ASR and (3) the effects of the CRF2 receptor agonist urocortin 2 (0.2-6 nmol, ICV) on ASR in mice. RESULTS: h/r-CRF significantly increased ASR in mice in a time-dependent manner with maximal efficacy at the 0.2 and 0.6 nmol doses. 129S6/SvEvTac mice exhibited a slightly increased duration of action and lower minimal effective dose threshold for CRF effects on ASR compared to C57BL/6J mice. Both selective CRF1)and CRF2)antagonists attenuated h/r-CRF-potentiated ASR without affecting acoustic startle when given alone. The selective CRF2 receptor agonist urocortin 2 increased ASR (1 and 2 nmol), albeit with less efficacy than the non-selective CRF receptor agonist h/r-CRF. CONCLUSIONS: Both CRF1 and CRF2 receptors appear to contribute to the h/r-CRF-induced increases in ASR in mice. These data support the hypothesis that both receptors contribute to the anxiogenic effects of CRF.
RATIONALE: Hypersecretion of corticotropin releasing factor (CRF) has been implicated in both severe anxiety disorders and major depression. Although the role of the CRF1 receptor in the anxiogenic effects of CRF is well supported, the role of CRF2 receptors in anxiety-like behaviors is less clear. In rats, CRF increases the acoustic startle reflex (ASR) via its action in the extended amygdala, providing a putative measure of CRF-mediated anxiogenic activity. OBJECTIVE: To characterize the effect of CRF on ASR in mice and determine the respective roles of CRF1 and CRF2 receptors in CRF-potentiated ASR. METHODS: The present study examined: (1) the time course and dose response functions for the effects of human/rat (h/r)-CRF (0.02-0.6 nmol, ICV (intracerebroventricular)) on ASR in two inbred strains of mice; (2) the effects of the CRF1 receptor antagonist NBI-30775 (20 mg/kg, intraperitoneal) and the CRF2 receptor antagonist Antisauvagine-30 (1-10 nmol, ICV) on CRF-potentiated ASR and (3) the effects of the CRF2 receptor agonist urocortin 2 (0.2-6 nmol, ICV) on ASR in mice. RESULTS: h/r-CRF significantly increased ASR in mice in a time-dependent manner with maximal efficacy at the 0.2 and 0.6 nmol doses. 129S6/SvEvTac mice exhibited a slightly increased duration of action and lower minimal effective dose threshold for CRF effects on ASR compared to C57BL/6J mice. Both selective CRF1)and CRF2)antagonists attenuated h/r-CRF-potentiated ASR without affecting acoustic startle when given alone. The selective CRF2 receptor agonist urocortin 2 increased ASR (1 and 2 nmol), albeit with less efficacy than the non-selective CRF receptor agonist h/r-CRF. CONCLUSIONS: Both CRF1 and CRF2 receptors appear to contribute to the h/r-CRF-induced increases in ASR in mice. These data support the hypothesis that both receptors contribute to the anxiogenic effects of CRF.
Authors: T M Reyes; K Lewis; M H Perrin; K S Kunitake; J Vaughan; C A Arias; J B Hogenesch; J Gulyas; J Rivier; W W Vale; P E Sawchenko Journal: Proc Natl Acad Sci U S A Date: 2001-02-27 Impact factor: 11.205
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